Serotonin (5-hydroxytryptamine, 5-HT) plays a significant role in influencing a large number of central and peripheral processes. 5-HT-selective pharmacotherapies have been developed to treat a wide variety of medical problems including depression, anxiety, schizophrenia, migraine, emesis, and appetite control (Annual Reports in Medicinal Chemistry, Volume 32, 2002, Academic Press, Fitzgerald, L., Ennis, M. “5-HT2C Receptor Modulators: Progress in Development of New CNS Medicines” pp 21-30). 5-HT exerts its influence through activation of fourteen distinct receptor subtypes in seven separate families. There is particular interest in the three receptor subtypes of the 5-HT2 family, 5-HT2A, 5-HT2B, and 5-HT2C. Modulation of the 5-HT2C receptor subtype has been shown to play a role in numerous human diseases including obesity, obsessive-compulsive disorder (OCD), sexual dysfunction, epilepsy, schizophrenia, and anxiety disorders (Roth, B., Shapiro, D. “Insights into the Structure and Function of 5-HT2 Family Serotonin Receptors Reveal Novel Strategies for Therapeutic Target Development” Expert Opin. Ther. Targets 2001, 5, 685; Martin, J., Bos, M., Jenck, F., Moreau, J-I., Mutel, V., Sleight, A., Wichmann, J., Andrews, J., Berendsen, H., Broekkamp, C., Ruight, G., Kohler, C., van Delft, A. “5-HT2C Receptor Agonists: Pharmacological Characteristics and Therapeutic Potential” J. Pharm. Experimental Ther. 1998, 286, 913). However, the transmembrane sequence homology between the 5-HT2C receptor and the 5-HT2A and 5-HT2B receptors is high (Bickerdike, M., Vickers, S., Dourish, C. “5-HT2C Receptor Modulation and the Treatment of Obesity” Diabetes Obes. Metab. 1999, 1, 207; Glennon, R., Dukat, M., El-Bermawy, M., Law, H., De Los Angeles, J., Teitler, M., King, A., Herrick-Davis, K. “Influence of Amine Substituents on 5-HT2A versus 5-HT2C Binding of Phenylalkyl- and Indolylalkylamines” J. Med. Chem. 1994, 37, 1929). Thus selectivity for the 5-HT2C receptor can be difficult to obtain, however such selectivity is important from a drug development standpoint. 5-HT2B receptor agonists are associated with heart valve toxicity (Rothman, R., Baumann, M., Savage, J., Rauser, L., McBride, A., Hufeisen, S., Roth, B. L. “Evidence for Possible Involvement of 5-HT2B Receptors in the Cardiac Valvulopathy Associated with Fenfluramine and other Serotonergic Medications” Circulation 2000, 102, 2836; Fitzgerald, L., Burn, T., Brown, B., Patterson, J., Corjay, M., Valentine, P., Sun, J-H., Link, J., Abbaszade, I., Hollis, J., Largent, B., Hartig, P., Hollis, G., Meunier, P., Robichaud, A., Robertson, D. “Possible Role of Valvular Serotonin 5-HT2B Receptors in the Cardiopathy Associated with Fenfluramine” Molecular Pharmacology 2000, 57, 75) and pulmonary hypertension (Launay, J., Herve, P., Peoc'h, K., Tournois, C., Callebert, J., Nebigil, C., Etienne, N., Drouet, L., Humbert, M., Simonneau, G., Maroteaux, L. “Function of the Serotonin 5-Hydroxytryptamine 2B Receptor in Pulmonary Hypertension” Nat. Med. 2002, 8, 1129). However, the 5-HT2C receptor is found only in the CNS (Bickerdike, M., Vickers, S., Dourish, C. “5-HT2C Receptor Modulation and the Treatment of Obesity” Diabetes Obes. Metab. 1999, 1, 207; Martin, J., Bos, M., Jenck, F., Moreau, J-I., Mutel, V., Sleight, A., Wichmann, J., Andrews, J., Berendsen, H., Broekkamp, C., Ruight, G., Kohler, C., van Delft, A. “5-HT2C Receptor Agonists: Pharmacological Characteristics and Therapeutic Potential” J. Pharm. Experimental Ther. 1998, 286, 913), and agonists that discriminate for 5-HT2C over 5-HT2B should not display cardio- or pulmonary toxicity. Selectivitiy for 5-HT2C over 5-HT2A receptors is also important since agonists at 5-HT2A generally display undesirable hallucinogenic activity (e.g. LSD, psilocybin).
Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is an agonist at the 5-HT2A and 5-HT2C receptors. Its binding potency at 5-HT2A correlates with its activity as a hallucinogen in humans (Delgado, P. L., Moreno, F. A. “Hallucinogens, Serotonin, and Obsessive-Compulsive Disorder” J. Psychoactive Drugs 1998, 30, 359; Perrin, D. M. “Hallucinogens and Obsessive-Compulsive Disorder” Am. J. Psychiatry 1999, 156, 1123; Moreno, F. A., Delgado, P. L. “Hallucinogen-Induced Relief of Obsessions and Compulsions” Am. J. Psychiatry 1997, 154, 1037). More than 40 years ago, some derivatives of psilocybin were reported by workers at Sandoz (Hofmann, A., Troxler, F. U.S. Pat. No. 3,075,992; U.S. Pat. No. 3,078,214). This work was carried out prior to the ability to test for activity at specific serotonin receptor subtypes. More recently, considerable effort has been made in seeking selective 5-HT2C receptor ligands. The indole Ro 60-0175 (Martin, J., Bos, M., Jenck, F., Moreau, J-I., Mutel, V., Sleight, A., Wichmann, J., Andrews, J., Berendsen, H., Broekkamp, C., Ruight, G., Kohler, C., van Delft, A. “5-HT2C Receptor Agonists: Pharmacological Characteristics and Therapeutic Potential” J. Pharm. Experimental Ther. 1998, 286, 913; Bos, M., Jenck, F., Martin, J., Moreau, J-I., Sleight, A., Wichmann, J., Widmer, U. “Novel Agonists of 5-HT2C Receptors. Synthesis and Biological Evaluation of Substituted 2-(Indol-1-yl)-1-methylethylamines and 2-(Indeno[1,2-b]pyrrol-1-methylethylamines Improved Therapeutics for Obsessive Compulsive Disorder” J. Med. Chem. 1997, 45, 2762) is 25 times more active at 5-HT2C as compared to 5-HT2A, however it is not selective over 5-HT2B receptors (Bickerdike, M., Vickers, S., Dourish, C. “5-HT2C Receptor Modulation and the Treatment of Obesity” Diabetes Obes. Metab. 1999, 1, 207). Certain 1-methyl-5-substituted indoles reported by Lilly are selective 5-HT2B antagonists (Audia, J., Evrard, D., Murdoch, G., Droste, J., Nissen, J., Schenck, K., Fludzinski, Z., Lucaites, V., Nelson, D., Cohen, M. “Potent, Selective Tetrahydro-β-carboline Antagonists of the Serotonin 2B (5HT2B) Contractile Receptor in the Rat Stomach Fundus” J. Med. Chem. 1996, 39, 2773). Substituted indoles were reported by Vernalis to be highly selective agonists at 5-HT2C as compared to 5-HT2A (American Chemical Society National Meeting, Boston, Mass., Aug. 18-22, 2002, Poster Session, Division of Medicinal Chemistry, Wednesday morning, August 21, #344-349). Wyeth has reported 5-HT2C agonists including WAY161503 that are active in an animal model of obesity (Welmaker, G., Nelson, A., Sabalski, J., Sabb, A., Potoski, J., Graziano, D., Kagan, M., Coupet, J., Dunlop, J., Mazandarani, H., Rosenzwieg-Lipson, S., Sukoff, S., Zhang, Y. “Synthesis and 5-hydroxytryptamine (5-HT) activity of 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5-(6H)ones and 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxalines” Bioorg. Med. Chem. Lett. 2000, 10, 1991). Yamanouchi has described indazole compounds including YM348 which are 5-HT2C agonists showing activity in an animal model of obesity (Kimura, Y., Hatanaka, K., Naitou, Y., Maeno, K., Shimada, I., Koakutsu, A., Wanibuchi, F., Yamaguchi, T., “Pharmacological profile of YM348, a novel, potent and orally active 5-HT2C receptor agonist” Eur. J. Pharmacol. 2004, 483, 37). Arena reports mCPP analogs active in vivo as potential obesity treatments (Smith, B., Smith, J., Tsai, J., Schultz, J., Gilson, C., Estrada, S., Chen, R., Park, D., Prieto, E., Gallardo, C., Sengupta, D., Thomsen, W., Saldana, H., Whelan, K., Menzaghi, F., Webb. R., Beeley, N. “Discovery and SAR of new benzazepines as potent and selective 5-HT(2C) receptor agonists for the treatment of obesity” Bioorg. Med. Chem. Lett. 2005, 15, 1467).
Obesity is one of the most important health problems currently affecting the U.S. population. The overweight suffer a significantly higher death rate, as well as a much greater risk of developing many diseases including type 2 diabetes, sleep apnea, hypertension, osteoarthritis, and some forms of cancer. Exercise and diet modification allow some obese people to lose weight. However, many others are unable to achieve lasting weight loss by such methods, and pharmaceutical agents that promote satiety can be effective and appropriate treatments.
Considerable evidence has accumulated implicating 5-HT2C receptor activation with appetite suppression. In 1995, transgenic mice lacking the 5-HT2C receptor were shown to become obese (Tecott, L., Sun, L., Akana, S., Strack, A., Lowenstein, D., Dallman, M., Julius, D. “Eating Disorder and Epilepsy in Mice Lacking 5-HT2C Serotonin Receptors” Nature 1995, 374, 542). A clinical study in 1997 (Sargent, P., Sharpley, A., Williams, C., Cowen, P. “5-HT2C-Receptor Activation Decreases Appetite and Body Weight in Obese Subjects” Psychopharmacology 1997, 133, 309) using meta-chlorophenylpiperazine (mCPP), a 5-HT2C agonist, has shown appetite reduction and weight loss in obese subjects. Furthermore, selective 5-HT2C antagonists reduce or eliminate the anorexic effects of 5-HT2C agonists (Kennett, G., Wood, M., Bright, F., Trail, B., Riley, G., Holland, K., Avenell, K., Stean, T., Upton, N., Bromidge, S., Forbes, I., Middlemiss, D., Blackburn, T. “SB242082, a Selective and Brain Penetrant 5-HT2C Receptor Antagonist” Neuropharmacology, 1997, 36, 609). Fenfluramine is a non-selective 5-HT2C receptor agonist which together with phenteramine (“phen-fen”) was marketed until recently as a highly effective appetite suppressant. The clinical effectiveness of fenfluramine as an appetite suppressant has been shown to be largely due to its activity as a 5-HT2C receptor agonist (Bickerdike, M., Vickers, S., Dourish, C. “5-HT2C Receptor Modulation and the Treatment of Obesity” Diabetes Obes. Metab. 1999, 1, 207; Vickers, S., Dourish, C., Kennett, G. “Evidence that Hypophagia Induced by d-Fenfluramine and d-Norfenfluramine in the Rat is Mediated by 5-HT2C Receptors” Neuropharmacology 2001, 41, 200).
Obsessive Compulsive Disorder (OCD) is a mental illness involving persistent and distressing thoughts and actions that significantly interfere with normal life. OCD afflicts at least 1-2% of the population in the US and worldwide, and is the fourth most common psychiatric diagnosis in the United States (Delgado, P. L., Moreno, F. A. “Hallucinogens, Serotonin, and Obsessive-Compulsive Disorder” J. Psychoactive Drugs 1998, 30, 359; Goodman, W. K. “Obsessive-Compulsive Disorder: Diagnosis and Treatment” J. Clin. Psychiatry 1999, 60 (Suppl 18), 27). OCD is currently treated pharmacologically and/or with psychotherapy. Current pharmacotherapy for OCD has significant limitations and the discovery of an improved medication for OCD would have considerable commercial potential.
Psilocybin, a 5-HT2C receptor agonist, is currently in a Phase I clinical trial with OCD patients (The New York Times, Page D1, Mar. 13, 2001). Other 5-HT2C receptor agonists are recognized as potential treatments for OCD (Martin, J., Bos, M., Jenck, F., Moreau, J-I., Mutel, V., Sleight, A., Wichmann, J., Andrews, J., Berendsen, H., Broekkamp, C., Ruight, G., Kohler, C., van Delft, A. “5-HT2C Receptor Agonists: Pharmacological Characteristics and Therapeutic Potential” J. Pharm. Experimental Ther. 1998, 286, 913).
Other possible uses for 5-HT2C selective compounds include treatments for epilepsy (Isaac, M. “Serotonergic 5-HT2C Receptors as a Potential Therapeutic Target for the Design Antiepileptic Drugs” Current Topics in Medicinal Chemistry, 2005, 5, 59), Alzheimer's disease (Arjona, A., Pooler, A., Lee, R., Wurtman, R. “Effect of a 5-HT(2C) Serotonin Agonist, Dexnorfenfluramine, on Amyloid Precursor Protein Metabolism in Guinea Pigs” Brain Res. 2002, 951, 135), sexual dysfunction (Uckert, S., Stief, C., Jonas, U. “Current and Future Trends in the Oral Pharmacotherapy of Male Erectile Dysfunction” Expert Opin. Investig. Drugs 2003, 12, 1521; Millan, M., Peglion, J., Lavielle, G., Perrin-Monneyron, S. “5-HT2C Receptors Mediate Penile Erections in Rats: Actions of Novel and Selective Agonists and Antagonists” Eur. J. Pharmacol. 1997, 325, 9), and substance abuse and addiction disorders (Kampman, K., Pettinata, H., Lynch, K., Sparkman, T., O'Brien, C “A Pilot Trial of Olanzapine for Cocaine Dependence” Drug Alcohol Depend. 2003, 70, 265).
Compounds that are selective for the 5-HT2C receptor may therefore have therapeutic potential in treating, for example, the above disorders. Such selectivity can also reduce possible side effects due to activity at other serotonin receptors.
Certain N-unsubstituted psilocin derivatives containing fluorine substitution at the 5-, 6-, or 7-position have been reported (Blair, J., Kurrasch-Orbaugh, D., Marona-Lewicka, D., Cumbay, M., Watts, V., Barker, E., Nichols, D. “Effect of Fluorine Substitution on the Pharmacology of Hallucinogenic Tryptamines” J. Med. Chem. 2000, 43, 4701), and some of these compounds were shown to have reduced activity at the 5-HT2A receptor as compared to psilocin itself.